Lysosomal enzyme tripeptidyl peptidase 1 plays a role in degradation of beta amyloid fibrils

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques surrounded by microglia. In cell culture, microglia internalize fibrillar β-amyloid but do not degrade it efficiently. Unactivated microglia have a relatively high lysosomal pH, which impairs the activity of lysosomal proteases. Previous studies showed that activation of microglia with macrophage colony stimulating factor decreases lysosomal pH and enhances fibrillar β-amyloid degradation. We investigated the role of the lysosomal protease tripeptidyl peptidase 1 (TPP1) in cell culture and in a mouse model of Alzheimer’s disease. Increased levels of TPP1 in unactivated microglia enhanced fibrillar β-amyloid degradation. Conversely, reduction of TPP1 led to decreased fibrillar β-amyloid degradation in activated microglia, macrophages, and other cells that degrade fibrillar β-amyloid efficiently. Reduction of TPP1 in an AD model mouse using a gene-targeted hypomorphic Tpp1 allele increased plaque burden. These results suggest that decreased TPP1 potentiates AD pathogenesis and that strategies to increase TPP1 activity may have therapeutic value. Highlights *In microglia, TPP1 is important for the degradation of fibrillar β-amyloid. *Increased TPP1 in microglia results in enhanced fibrillar β-amyloid degradation. *In an AD mouse model, reduction of TPP1 led to increased amyloid plaque deposition.